U N S A T U R A T E D A C I D S AND M A C R O C Y C L I C L A C T O N E S

C O M M U N I C A T I O N 6. T R I - AND T E T R A - A C E T Y L E N I C

M A C R O C Y C L I C L A C T O N E S AND THE C O R R E S P O N D I N G POLYENES

L. D. B e r g e l ' s o n and Y u l . G. M o l o t k o v s k i i

Institute for the Chemistry of Natural Products, Academy of Sciences, USSR Translated from Izvestiya Akademii Nauk SSSR, Otdelenie Khimicheskikh Nauk, No. 1, pp. 105-112, January, 1963 Original article submitted May 7, 1962

A few years ago a large group of polyenic antibiotics,which arise as metabolites from various streptomyces (see review in [1]), was discovered. It was shown recently that some of these substances are unsaturated macro- cyclic lactones [2-5]. In view of the closeness in biological and physical properties between the polyenie anti- biotics, it is probable that most of the other compounds of this class (at the present time they already number about fifty) are also macrolides. The peculiar feature of the antibiotic action of the polyenie macrolides is their high ac. tivity with respect to pathogenic molds and yeasts and their low activity with respect to bacteria. In view of this, they have acquired importance in the treatment of fungal disorders due to a disturbance of biological equilibrium in the organism under the action of tetracyclines, streptomycin, and other widely used antibiotics.

In a study of ways of synthesizing unsaturated macrolides we recently developed a method of preparing diace- tylenic maerocyclic laetones by the oxidative condensation of w,w'-diaeetylenic esters [6]:

(CH~)m CHRC ~ CH HC ~ C (CH~)n CO -~ CHRC~CC--~C(CH~)n CO I o . . . . . . . . . . I (~Ih),~o. , [

We now describe the synthesis of tri- and tetra-acetylenic macrocyclic laetones and the corresponding poly- enes*. As the C atoms of tri- and tetra-aeetylenic groupings are disposed in a straight line, they can be included in the macroeyclic system only when this is considerably enlarged. We carried out the synthesis of the smallest cycles of this type that are able to exist without strain: 19-membered triaeetylenic and 24-membered tetraacety- lenic iactones. For the synthesis of a triaeetylenic lactone 9-chlorononanoic acid was esterified with 4-pentyn- l -o l , and the resulting chloro ester (I; X = C1) was converted into the corresponding iodo derivative (I; X = I) by boiling it with sodium iodide in butanone. The condensation of this with the monosodium derivative of butadiene in liquid ammonia led to 4-pentynyl 10,12- tridecadiynoate (II). As this compound was found to be unstable (it darkens within 2-3 minutes when exposed to light), it was not isolated, but in admixture with the original iodo ester (I; X = I) it was subjected to oxidative condensation under high-dilution conditions. The structure of the then formed 10,12,14- octadecatriynolide [18'hydroxy-10,12,14-octadecatriynoie ]actone] (III) was confirmed by its ultraviolet spectrum (see Table 1) (of. [8]) and its reduction to the known octadecanolide [9].

X(CH~)~COO(CH~)~CECll (i)

_- C 2c-cc~-cc-ccH~-~') (CH,z) 7 CO0 ( CH~)~, - ' - - ' /

I l l l~

- HC.,---- CG--C (CH~)~r OOICH~) 3~I- I ' - - - -" (n)

H~ r r ~ H H%r~C/H

(CH2), CO0( C-H2~. 2 - (w)

* For preliminary communication, see [7].

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~ t H H I

_ .

" , ) ' (CH2) 7COO(CH2) r i .

(V)

The starting compound for the synthesis of the tetraacetylenic lactone was the w,~o'-diiodo ester (VI; X : I), which was prepared by the reaction ll-chloroundecanoyl chloride with tetrahydrofuran in presence of zinc chloride [10] and subsequent boiling with sodium iodide. On condensation with the monosodium derivative of butadiyne, the diiodo ester (VI; X = I) formed 5,7-oetadiynyl 12,14-pentadeeadiynoate (VII) in admixture with iodine-containing compounds. After oxidative condensation of this mixture of substances and chromatography of the reaction products on alumina we isolated crystalline 12,14,16,18-tricosatetraynolide (VIII), which had an ultraviolet spectrum charac- teristic for conjugated tetraynes [11] (see table) and on hydrogenation formed the known saturated Cz3 lactone trieo- sanolide [9].

Principal Ultraviolet Maxima of Unsaturated Macrocyclic La ctones

i ' l : J

o Xma x (m.) /e

11I IV V

VIlI IX X

214/126 000 * 263, 273, 284/34500, 42000, 30700** 259, 269, 280/40300, 47400, 33600** 218, 229, 24t/63800, 166000, 257000* 292, 305, 3t9/55800, 71300, 55500** 287, 30t, 316/59000, 85100, 73100**

The selective hydrogenation of the tri- and tetra-acetylenic lactones (III) and (VIII) to the corresponding polyenes (IV) and (IX) is associated with considerable difficulties, because Lindlar's catalyst [12] is not sufficiently selective under the usual condi- tions toward polyacetylenes (hydrogenation does not slow down appreciably after the absorption of the amount of hydrogen re- quired for the conversion of the triple bonds into double). As a result of a series of experiments in which reduction was followed with the aid of ultraviolet spectra, we succeeded in raising the yield of polyenes by carrying out the

* In alcohol. ** In heptane.

H\. /tl H\ /H / C - ~ C , . / C = C . . /CHw-. .

" - = (CH2)gCOu(CH:2).r " - ' ~ (CH2)9COO (CH2)a (vm,) (rx)

H H, H H I / T /

(CH2)9COO (Ctl,)~ - - J " (X)

hydrogenation over Lindlar's catalyst in presence of quinoline a t - 1 0 ~ However, even under these conditions the hydrogenation was far from selective and led to complex mixtures containing, not only the polyenie lactones (IV) and (IX), but also unchanged polyaeetylenes and products of their partial and exhaustive hydrogenation. The chromato- graphic separation of these mixtures was complicated by the fact that the polyenic laetones (IV) and (IX), unlike the corresponding polyacetylenes, are not eluted from neutral alumina unless the latter is strongly deactivated. By the use of 300-500 times the amount of neutral low-activity alumina we succeeded in isolating crystalline 10,12,14-oc- tadecatrienolide (IV) and 12 ,13 ,16 ,18- tricosatetraenolide (IX), in which, judging from the infrared spectra (absence

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of absorption in the 900-1000 cm "~ region), all the double bonds have the cis contigurauon, ~nls wew was con-

firmed by the isomerization of the cis lactones (IV) and (IX) in a brief ultraviolet irradiation in presence of iodine, The three ultraviolet maxima were then shifted by 4 mY toward the short waves with increase in the extinction co- efficient, which indicates isomerization of the cis trienes and cis tetraenes into polyenes containing trans ethylenic bonds (see table). The question of the configurations of the isomerization products remains open, but data obtained in the isomerization of aliphatic polyenes under analogous conditions [13, 14] enable us to suppose that the isomer- ized lactones are the "all trans" forms (V) and (X). It is interesting that the "all cis" tetraenie lactone (IX) is very unstable and, judging from the Ultraviolet spectrum, already undergoes change on standing in diffuse light in a ni- trogen atmosphere for a few minutes.

Microbiological study of the polyacetylenic and polyenic laetones ( I I I ) - (V) and (VIII)- (X) showed that they have scarcely any antifungal and antibacterial action*. This fact may be associated with the negligible solubility of these lactones in polar media, for it has been found previously that the diacetylenic 23-membered lactone is also of low activity, whereas the corresponding 16- and 17-membered lactones show appreciable antimicrobial act ion[I5] ,

E X P E R I M E N T A L Melting points were determined in capillaries or on a Kofler block (KB) and were not corrected. Infrared spec-

tra were determined with ~ UR-10 spectrograph (Zeiss, East Germany)**. Ultraviolet spectra were determined with an SF-4 spectrograph, w-Chloro acid chlorides were prepared under previously described conditions [6],

4 - P e n t y n y l 9 - C h l o r o n o n a n o a t e ( I ; X = C1) . A solution of 28 ml of pyridine in 50 ml of ether was added dropwise at 10-15 ~ over a period of one hour to a solution of 59.6 g of 9-chlorononanoyl chloride [b.p. 116-118 ~ (0.5 mm); n~ 1.4637; d~ ~ 1.0043. Found: C 64.65; H 9.02; C1 13,75%; MR 71.06. C14I-~OzC1. C a l c u l a t e d C 64.97; H 8.96; C1 13.70%; MR 71.31.

4 - P e n t y n y l 9 - I o d o n o n a n o a t e ( I ; = X = I ) . A s o l u t i o n o f 6 3 . 8 g o f 4 - p e n t y n y l g - c h l o r o n o n a n o a t e (I; X = C1) and 57.5 g of sodium iodide in 600 ml of butanone was boiled for 15 hours; precipitated sodium chloride was filtered off, and solvent was distilled off. The residue was dissolved in 300 ml of ether, and the solution was washed with 5% sodium thiosulfate solution and twice with water; it was dried with magnesium sulfate. Solvent was distilled off, and crystallization from methanol gave 68.4 g (79%) of 4-pentynyl 9-iodononanoate, m.p. 15-17 ~ Found: I 35.94%. ClaH~O2I. Calculated: I 36.23%.

4 - C h l o r o b u t y l l l - C h l o r o u n d e c a n o a t e ( V I ; X = C1) , 50 ml of tetrahydrofuran was added with stirring and cooling with cold water over a period of 40 minutes to 82 .5gof l l -ch loroundecanoyl chloride [b.p. 110-112 ~ (0,3 ram)] and 1.5 g of zinc chloride at such a rate that the temperature did not rise above 20*, Thismix- ture was stirred further for eight hours at 7ff and cooled; 150 ml of benzene was added, and the solution was washed successively with water, with saturated sodium bicarbonate solution, and with saturated brine; it was dried with mag- nesium sulfate. Solvent was distilled off, and vacuum distillation gave 100.6 g (94%) of a colorless oil; b.p, 148-150 ~ (0,3 mm); n~ 1.4646; d4 ~ 1.0390, Found: C 57, 75; H 9,00; C1 22.7690; MR 82,77. C15H~sO2CI~. Calculated: C57.88; H 9.07; C1 22.78%; MR 82.86.

4 - I o d o b u t y l 1 1 - I o d o u n d e c a n o a t e ( V I ; X = I ) . Under the conditions for the synthesis of the iodononanoic ester (I; X = I), from 43 g of 4-chlorobutyl l l -ch loroundecanoa te (VI; X = C1) we obtained 52,7 g (77%) of the w,w'-di iodo ester (VI; X = I) as colorless crystals, m.p. 24-25 ~ (from ethanol). Found: I 51,36~ C15H2sO2I 2. Calculated I 51.36%.

1 0 , 1 2 , 1 4 - O e t a d e c a t r i y n o l i d e ( I I I ) . 2.34 g of l ,4-d iehloro-2-butyne [17] i n10 ml of ether was added over a period of ten minutes a t - 7 0 " in a stream of nitrogen to a suspension of sodamide prepared from 1.26 g of sodium in 200 ml of liquid ammonia, and then 5 g of 4-pentynyl 9-iodononanoate was added over a period of ten minutes. The mixture was stirred for two hours a t - 7 0 ~ and for six hours a t - 3 5 ~ 3,5 g of ammonium chloride was then added, and ammonia was allowed to evaporate. 100 ml of ether and 25 ml of saturated ammonium sulfate solution were added to the residue, and the mixture was acidified m pH 6 with 3~o hydrochloric acid. The ether layer was separated, and the aqueous layer was extracted with two 100-ml portions of ether. The combined ether

* The microbiological investigation was carried out by I. D. Ryabova (Biological-testing Laboratory, Institute for the Chemistry of Natural Products, Academy of Sciences, USSR). ** Infrared spectra were determined by L. B. Senyavina,

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extracts were dried with magnesium sulfate and, to separate resinous substances, filtered through a 22. 150-ram column of alumina of Grade II activity and then through a 22 . 40-ram column of activated Charcoal (the columns were washed with 200 ml of ether). Solvent was distilled off, and the residue (2.2 g) was chromatographed through a 22 . 150-mm column of alumina of Grade III activity. After development with hexane (100 ml), 1,43 g of a colorless oil, which rapidly darkened when exposed to light, was eluted with a 6 : 1 mixture of hexane and ether (350 ml)* . The substance contained 5.5% of iodine, which corresponds to a content of 16% of unchanged 4-pentynyl 9-iodononanoate. The ultraviolet spectrum (determined in alcohol) had absorption maxima at 229, 241, and 251 m/a, characteristic for a conjugated diynic system [18]. The infrared spectrum (in petrolatum): 1736 (s) (earbonyl group), 2220 (m) (triple bond), and 3310 c m "1 (s) (ethynyl hydrogen).

A solution of 1.38 g of unpurified ester (II) in 20 ml of ether was added (through a high-dilution head fitted w'ith a spray doser to give uniform feed [19]) to 700 ml of a boiling 3 : 2 mixture of pyridine and ether (temperature 56-57 ~ containing 6 g of copper acetate. The addition continued for four hours, after which the mixture was stirred further for 20 minutes, cooled to 15", and filtered through 200 g of alumina of Grade II activity to remove copper sa!ts; the column was washed with 250 ml of a 3 : 1 mixture of ether and pyridine. The solution was vacuum-eva- porated down to 25 ml, diluted with 150 ml of ether, and poured into a mixture of ice and 700 ml of 3% hydrochloric acid. The ether layer was separated, and the aqueous layer was extracted with three 100-ml portions of ether. The combined extracts were dried with magnesium sulfate, solvent was distilled off, and the residue was chromatographed through a 22 . 100-ram eoiumn of alumina of Grade It activity. After development of the column with petroleum ether (!00 ml), with a 6 : 1 mixture of hexane and ether we etuted 500 mg of a crystalline substance, from which after crystallization from hexane we obtained 410 mg of colorless crystals, m.p. 68-69 ~ with decomposition (KB). The yield of 10,12,14-octadecatriynolide (III) was 1t% (based on the 4-pentynyl 9-iodononanoate). Ultraviolet spec- trum (in alcohol): ) 'max 214, 240, 256,272, 292,312 mbt (~ 126000, 453, 162 ,200 ,234 , 166). Infrared spectrum (in petrolatum): Umax 1733 (s) (carbonyl group), 2218 (s) triple bond), 1165 cm "1 (s) ( C - O - C grouping). Found: C 80.20; H 8.41%. C1sH220~. Calculated: C 79.96: H 8.20%.

1 2 , 1 4 , 1 6 , 1 8 - T r i c o s a t e t r a y n o l i d e ( V I I I ) . The synthesis was carried out analogously to the above. By the condensation of 50 g of 4-iodobutyl l l - iodoundecanoa te (VI, X = I) with the monosodium derivative of buta- diyne (from 16.9 g of sodium and 30.8 g of 1 ,4-dichloro-2-butyne) we obtained 16.4 g of a yellowish oil, which rap- idly darkened when exposed to light. Ultraviolet spectrum (in alcohol: Xma x 228, 239, 252 m p , Infrared spectrum (in petrolatum): u max 1733 (s) (carbonyl group),2055 (w), 2220 (s), and 2300 ( m ) (triple bond), 3310 c m "~ (s) (ethy- nyt hydrogen), ludging from the spectrum, the product contained the bisdiacetylenic ester (VII), but the results of thin-layer chroma tography and of elementary analysis (found: I 11.7%) showed that iodine- containing substances were present.

On macroeycl izat ion of 0.24 g of this oil with subsequent chromatography on alumina and crystalIization from a I : 1 mixture of ether and hexane we isolated 30 mg of 12,14,16,18-trieosatetraynolide (Viii) as colorless crystals, m.p. 105-106 ~ with decomposition (KB). Yield 6% (based on 4-iodobuyfl l l - iodoundecanoate) . Ultraviolet spec- trum (in alcohol): Xma x 218, 229, 241, 2 8 8 , 3 0 9 , 3 3 0 , 356, m/~ ( e 63800, 166000, 257000, 221,231, 228, 153), Infrared spectrum (in petrolatum): u max 1730 (s) (carbonyl group), 2215 cm -1 (s) (triple bond), Found: C 82.25; H 8.49~./'oo Cz~H280 z. Calculated C 82.10; H 8.39%.

t 0 , 1 2 , 1 4 - O c t a d e e a tr i e rl ol i d e ( I V) . 58 mg of 10,12,14-octadecatriynolide was hydrogenated in 15 ml of hexane over 20 mg of Lindlar's catalyst [12] and 5 mg of quinoline a t - 1 0 * . In the course of two hours 106% of the theoretically calculated amount of hydrogen had been absorbed and the rate of hydrogenation had been ap- proximately halved. Hydrogenation was stopped, the catalyst was filtered off, and the mixture was washed with 1% hydrochloric acid, with water, and with saturated ammonium sulfate solution. Solvent was distilled off, and the residue was chromatographed through a 14 �9 160-ram Column of alumina of Grade IV activity in isopentane, taking 15-ml fractions whose contents were checked by their ultraviolet spectrum. Fractions IV, V, ~nd VI contained 16.5 mg (28%) of colorless crystals. After recrystallization from isopentane we obtained the triene (IV), m.p. 54-56 ~ (KB). For the ultraviolet spectrum see the table, Infrared spectrum (in petrolatum): u max 722 (m) (cis hydrogens at a double bond), 1732 cm "~ (s) (carbonyl group). There was no absorption in the 900-1000 cm -~ range. Found: C 78.19; H 10.34%. C18H2802. CMculated: C 78,21; H 10.21%. On the microhydrogenation of 1.6 mg of the triene (IV) over a platinum catalyst in alcohol, 0.43 ml of hydrogen at 18 ~ and 748 mm was absorbed, which was 102% of the amount calcul2ted theoretically.

�9 The course of the chromatography was followed with the aid of thEn-layer chromatography on alumina.

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1 2 , 1 4 ,1 6,1 8 - T r i c o s a t e t r a e n o I i d e ( I X ). 98 mg of 12,14,16,18- tricosatet~aynolide (VIII) was hy- drogenated in 15 ml of ethyl acetate over 30 mg of Lindlar's catalyst and 20 mg of quinolinc a t - 1 0 ~ In the course of 2.5 hours 94% of the theoretical amount of hydrogen was absorbed and the rate of hydrogenation had been reduced to one-tenth of its initial value. Catalyst was filtered off,and the solution was diluted with 20 ml of hexane and washed with I~ He1, with water, and with saturated ammonium sulfate solution. Solvent was vacuum-distilled off, and the residue was chromatographed through a 14 . 160-mm column of alumina (Grade IV activity) in isopentane; 15-ml fractions were collected, and their compositions were checked by their ul~aviolet spectra. Fractions V-VIII contained 16.6 mg (16a]o) of a tetraenic lactone, which formed colorless crystals, m.p. 23-25* (KB). For the ultra- violet spectr/im, see table. The infrared spectrum (in petrolatum) had u max 715 (m) (cis hydrogens at a double

bond), 1737 cm "I (s) (carbonyl group). There was no absorption in the 900-1000 cm "! region. Found C 80.10; H 10.51~o. C~Hs60 ~. Calculated: C 80.18; H 10.53%.

E x h a u s t i v e H y d r o g e n a t i o n of the L a c t o n e s ( I l l ) and ( V I I I ) . 50 mgof10,12,14-octadeca- triynolide (Ill) was hydrogenated in 5 ml of dioxane over a platinum catalyst until absorption of hydrogen ceased; the product was filtered, and the filtrate was evaporated. Vacuum fractionation of the residue at a bath temperature of 150" and a residual pressure of 0.3 mm gave, after crystallization from alcohol, octadecanolide, m.p. 36-38* (the literature [9] gives m.p. 36-37*), Found: C 76.54; H 12.149o. CIsH~4Og. Calculated C 76,54; H 12.139o.

I s o m e r i z a t i o n of the c is P o l y e n i c L a c t o n e s ( I V ) and ( I X ) . A solution of thepolyenic lac- tone in heptane containing la]o of iodine (on the weight of the substance) was irradiated for five minutes with a PRK-4 quartz lamp (nominal power 200 W). The ultraviolet spectra of the trans isomers obtained are given in the table.

SUMMARY 1. w-Diacetylenic esters were prepared by the condensation of w-haloalkanoic esters with the monosodium

derivative of butadiyne in liquid ammonia. In this way, from 4-pentynyl 9-chlorononanoate and 4-chlorobutyl 11- cbloroundecanoate, 4-pentynyl 10,12-tridecadiynoate and 5,7-octadiynyl 12,14-pentadecadiynoate, respectively, were obtained.

2. By the oxidative condensation of these esters under conditions of high dilution a 19-membered triacetylenic lactone and a 24-membered tetraacetylenic lactone were obtained and these were converted into the corresponding tri- and tetra-enic macrocyclic lactones by hydrogenation.

L I T E R A T U R E C I T E D 1. M.M. Shemyakin, A. S. I<hokhlov, M. N. Kolosov, L. D. 13ergel'son, and V. K. Antonov, Chemistry of Anti-

biotics[in Russian], Moscow (1961), pp. 88-112. 2. J.B. Patrick, R. P. Williams, and J. S. Webb, J. Amer. Chem. Soc. 80, 6689 (1958). 3. M.L. Dhar, V, Thaller, and M. C. Whiting, Proe. Chem. Soc. 1958, 148. 4. C. Djerassi, M. Ishikawa, H. Budzikiewicz, J. N. Schoolery, and L. F. Johnson, Tetrahedron Letters, 383 (1961). 5. E. Borowski and C. P. Schaffner, Fifth International Biochemical Conference, Abstracts of Section Communica-

tions, Vol. 1 [in Russian], Moscow (1961), p. 13. 6. L.D. Bergel'son, Yul. G. Molotkovskii, and M. M. Shemyakin, Zh. obshch, khimii 32, 58 (1962). 7. L.D. Bergel'son and Yul G. Molotkovskii, Izv. AN SSSR, Otd. khim. n. 1962,539. 8. J. B, Armitage, C1. Cook, E. R. H. Jones, .and M. C. Whiting, J. Chem. Soc. 1952,2010. 9. M. Stoll and A. Rouve, Helv. chim. acta 18, 1087 (1935).

10. L.M. Smorgonskii and Ya. L. Gol'dfarb, Zh. obshch, khimii 1..~0, 1113 (1940. 11. J.B. Armitage, E. R. H. Jones, and M. C. Whiting, J. Chem. Soe. 1952, 2014. 12. H. Lindlar, Helv. chim. acta 35 , 446 (1952). 13. L. Crombie and A. G. Jacklin, J. Chem. Soc. 1957,1632. 14. H.P. Kaufmann and P. K. Sud, Chem. Bet. 92, 2797 (1959). 15. L.D. Bergel'son, Yul. G. Molotkovskii, M. M. Shemyakin, M. M. Levitov, and Yu. O. Sazykin, Antibiotics

[in Russian], Medgiz, (1961), p. 581. 16. Organic Syntheses 33, 68 (1953). 17. A.W. Johnson, J. Chem. Soc. 1946, 1009. 18. J.B. Armitage, C. L. Cook, N. Entwistle, E. R. H. Jones, and M. C. Whiting, J. Chem. Soc. 1952)1998. 19. Ya. L. Gol'dfarb, S. Z. Taits, and L. I. Belen'kii, Zh. obshch, khimii 29, 3564 (1959).

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